Studies on individuals and animals with genetic defects in serotonin function can shed light on the role of this neurotransmitter in behavior and on the role of milder functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. We are identifying probands for family studies who have several behavioral disorders and by measuring the serotonin metabolite 5HIAA in cerebrospinal fluid. Probands and family members receive detailed neurologic and psychiatric assessment and familial transmission and comorbidity is concurrently assessed. Subjects with aberrant serotonin function and their families will be the focus for genetic linkage analyses using dispersed probes and direct studies (for example, sequencing) of candidate genes such as tryptophan hydroxylase (TPH). We are also studying animal behavioral genetic models in which serotonin function may be perturbed. A TPH polymorphism was found to be associated with low CSF 5HIAA and suicidality in impulsive alcoholic Finns. Coding sequence polymorphisms of 5HTIA, 5HTIDalpha and 5HTIDbeta were identified by SSCP analysis. In mice, TPH was identified as a quantitative trait locus (QTL) for sleep time following ethanol injection.